RT Journal Article
SR Electronic
T1 Carbamylation of Serum Albumin as a Risk Factor for Mortality in Patients with Kidney Failure
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 175ra29
OP 175ra29
DO 10.1126/scitranslmed.3005218
VO 5
IS 175
A1 Berg, Anders H.
A1 Drechsler, Christiane
A1 Wenger, Julia
A1 Buccafusca, Roberto
A1 Hod, Tammy
A1 Kalim, Sahir
A1 Ramma, Wenda
A1 Parikh, Samir M.
A1 Steen, Hanno
A1 Friedman, David J.
A1 Danziger, John
A1 Wanner, Christoph
A1 Thadhani, Ravi
A1 Karumanchi, S. Ananth
YR 2013
UL http://stm.sciencemag.org/content/5/175/175ra29.abstract
AB Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys549. The proportion of serum albumin carbamylated on Lys549 (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.